Levoleucovorin

CLINICAL PHARMACOLOGY

Mechanism Of Action

levoleucovorin is the pharmacologically active isomer of 5-formyl tetrahydrofolic
acid. levoleucovorin does not require reduction by the enzyme dihydrofolate
reductase in order to participate in reactions utilizing folates as a source
of “one-carbon” moieties. Administration of levoleucovorin can counteract
the therapeutic and toxic effects of folic acid antagonists such as methotrexate,
which act by inhibiting dihydrofolate reductase.

Pharmacodynamics

levoleucovorin is activelyand passivelytransported across cell membranes. In
vivo, levoleucovorin is converted to 5-methyltetrahydrofolic acid (5-methyl-THF),
the primary circulating form of active reduced folate.levoleucovorin and 5-methyl-THF
are polyglutamated intracellularly by the enzyme folylpolyglutamate synthetase.Folylpolyglutamates
are active and participate in biochemical pathways that require reduced folate.

Pharmacokinetics

The pharmacokinetics of levoleucovorin after intravenous administration of
a 15 mg dose was studied in healthy male volunteers. After rapid intravenous
administration, serum total tetrahydrofolate (total-THF) concentrations reached
a mean peak of 1722 ng/mL. Serum (6S)-5-methyl-5,6,7,8-tetrahydrofolate concentrations
reached a mean peak of 275 ng/mL and the mean time to peak was 0.9 hours. The
mean terminal half-life for total-THF and (6S)-5-methyl-5,6,7,8-tetrahydrofolate
was 5.1 and 6.8 hours, respectively.

Clinical Studies

The safety and efficacy of levoleucovorin rescue following high-dose methotrexate
were evaluated in 16 patients age 6-21 who received 58 courses of therapy for
osteogenic sarcoma. High-dose methotrexate was one component of several different
combination chemotherapy regimens evaluated across several trials. Methotrexate
12 g/m² IV over 4 hours was administered to 13 patients, who received levoleucovorin
7.5 mg every 6 hours for 60 hours or longer beginning 24 hours after completion
of methotrexate. Three patients received methotrexate 12.5 g/m² IV over
6 hours, followed by levoleucovorin 7.5 mg every 3 hours for 18 doses beginning
12 hours after completion of methotrexate. The mean number of levoleucovorin
doses per course was 18.2 and the mean total dose per course was 350 mg. The
efficacy of levoleucovorin rescue following high-dose methotrexate was based
on the adverse reaction profile. [See ADVERSE REACTIONS]

Last reviewed on RxList: 3/31/2008
This monograph has been modified to include the generic and brand name in many instances.